Senile plaques and neurofibrillary tangles (NFT) in cortical and subcortical regions occur consistently in middle-aged patients with Down's syndrome (DS). These abnormalities are believed to be identical to lesions that occur in nontrisomic individuals with Alzheimer's disease, but, in DS, these abnormalities are not invariably accompanied by dementia. The consistent appearance of deposits of amyloid and NFT in brains of individuals with DS in the third and fourth decades of life provides an extraordinary opportunity to investigate the time course of the development of brain abnormalities that occur in DS. In Project 3, we will use new approaches to delineate the evolution of age-associated cellular/molecular abnormalities that occur in these trisomic individuals. These studies are designed to clarify: The evolution of changes in the neuronal cytoskeleton; the role of gene expression in amyloidogenesis; temporal relationships of neuritic degeneration and deposition of amyloid senile plaques; the sequence of development of age- associated decrements of transmitter-specific markers in brains of individuals with DS; and relationships between cognitive/memory status and the frequency and distribution of brain abnormalities in these subjects. These studies utilize postmortem tissues form a group of patients who will patients who will have undergone chromosomal analysis and thorough serial clinical evaluations. Information derived from these studies will be very valuable in helping to interpret similar pathological/chemical abnormalities that occur, to a lesser extent, in aged individuals and, to a greater extent, in patients with Alzheimer's disease.